rs13312793

chr12-4370516-G-Achr12-4370516-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020638.3(FGF23):c.583C>T(p.Pro195Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,611,462 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: FGF23 NM_020638.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.83

Genes affected

FGF23 (HGNC:3680): (fibroblast growth factor 23) This gene encodes a member of the fibroblast growth factor family of proteins, which possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. The product of this gene regulates phosphate homeostasis and transport in the kidney. The full-length, functional protein may be deactivated via cleavage into N-terminal and C-terminal chains. Mutation of this cleavage site causes autosomal dominant hypophosphatemic rickets (ADHR). Mutations in this gene are also associated with hyperphosphatemic familial tumoral calcinosis (HFTC). [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain Fibroblast growth factor 23 (size 226) in uniprot entity FGF23_HUMAN there are 18 pathogenic changes around while only 3 benign (86%) in NM_020638.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010053068).
• BP6: Variant 12-4370516-G-A is Benign according to our data. Variant chr12-4370516-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 585858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00296 (449/151894) while in subpopulation AFR AF= 0.0103 (428/41412). AF 95% confidence interval is 0.00953. There are 3 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF23	NM_020638.3	c.583C>T	p.Pro195Ser	missense_variant	3/3	ENST00000237837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF23	ENST00000237837.2	c.583C>T	p.Pro195Ser	missense_variant	3/3	1	NM_020638.3	P1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 151776 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000620 AC: 153 AN: 246590 Hom.: 2 AF XY: 0.000455 AC XY: 61 AN XY: 134168

Gnomad AFR exome AF: 0.00866

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000256 AC: 373 AN: 1459568 Hom.: 3 Cov.: 33 AF XY: 0.000211 AC XY: 153 AN XY: 725732

Gnomad4 AFR exome AF: 0.00811

Gnomad4 AMR exome AF: 0.000695

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.00296 AC: 449 AN: 151894 Hom.: 3 Cov.: 31 AF XY: 0.00302 AC XY: 224 AN XY: 74250

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.000841 Hom.: 0

Bravo AF: 0.00334

ESP6500AA AF: 0.00662 AC: 29

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000775 AC: 94

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	This variant is associated with the following publications: (PMID: 18982401) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Autosomal dominant hypophosphatemic rickets Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Tumoral calcinosis, hyperphosphatemic, familial, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.62	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.069
MVP		0.94
MPC		0.31
ClinPred		0.0047	T
GERP RS		3.0
Varity_R		0.12
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13312793; hg19: chr12-4479682; COSMIC: COSV52977957;